The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP) are expressed in the early embryonic brain at the onset of neurogenesis, and are strongly induced in mature neurons in several experimental nerve injury. It is thus hypothesized that these peptides function in development and nerve regeneration. We propose here to utilize the facial nerve axotomy/crush paradigm as a model to investigate the regenerative actions of VIP and PACAP. Motor neuron survival and axon regeneration after injury will be compared in wild type mice vs. mice with targeted mutations in the VIP and PACAP genes. Injury-induced glial cell proliferation and activation, regulation of cytokine, growth factor and neurotrophic factor synthesis, and macrophage mobilization will also be examined. In addition, we will determine if the induction of extracellular matrix molecules and cell adhesion proteins purposed to be used substrates for axon regeneration is impaired in VIP and PACAP knockout mice. In conjunction with these studies, we will use an adenoviral vector systems to deliver PACAP to injured motor neurons. The latter approach will be used to rescue impaired responses in knockout mice, and to facilitate recovery in wild type mice. The results obtained with these in vivo approaches are expected to begin to reveal the specific mechanisms by which neuropeptides in this family regulate processes relevant to brain development and nerve injury.